COPD is an HIV-associated lung disease and a leading cause of morbidity and mortality. The mechanisms underlying HIV-associated COPD (HIV+COPD) are incompletely understood but HIV-specific or HIV-enhanced factors have been suggested as a substantial proportion of HIV+COPD occur in non-smokers and the disease typically develops at an earlier age than COPD in HIV-uninfected individuals. Our study will investigate a wide- range of potential mechanisms and a comprehensive set of biomarkers. We will use our IHOP cohort composed of HIV+ subjects who have recovered from pneumonia as studies indicate that these patients are at an especially high-risk for a greater decline in lung function and COPD. Our central hypothesis is that systemic immune activation and inflammation and functional PBMC defects characterized by shortened telomeres contribute to a greater decline in lung function in HIV+ individuals, and that microbial translocation may contribute to this process. Our preliminary data demonstrate a strong trend for shortened PBMC telomere length and elevated plasma IL-6 levels to be associated with COPD in our IHOP cohort. Aim 1: To test the hypothesis that short telomere length and/or low telomere length/telomerase activity (TL/TA) ratio in PBMCs and BAL are associated with an increased prevalence of COPD. Aim 2: To test the hypothesis that selected markers of immune activation and inflammation in plasma and BAL are associated with an increased prevalence of COPD. Aim 3: To validate the markers identified in Aims 1 & 2 in an ongoing multicenter, prospective HIV+ cohort and to test the hypothesis that the identified markers are associated with a greater decline in lung function (FEV1 and FEV1/FVC) and, as secondary aims, with a greater decline in DLco and development of COPD. Aims 1 & 2 will leverage the existing San Francisco IHOP cohort of >300 HIV+ subjects. We will conduct a cross-sectional, nested case-control study of 70 subjects with COPD and 140 subjects without COPD and analyze banked blood from an outpatient study visit for telomere length, TL/TA, and 12 markers of immune activation and inflammation, selected for their association with COPD in HIV- uninfected populations. We will investigate associations with HIV+COPD, adjusting for age, sex, and smoking and for multiple comparisons, and derive a set of candidate biomarkers to validate prospectively. As a sub-aim, we will also analyze these markers in BAL and compare them to blood from 50 HIV+ IHOP subjects with and without COPD undergoing serial bronchoscopies for an IHOP study. Aim 3 will use the ongoing IHOP cohorts in San Francisco, Seattle, and Kampala, Uganda. We will conduct a longitudinal cohort study of 600 HIV+ subjects recovered from pneumonia and analyze the markers identified in Aims 1 & 2 beginning >3 months after completion of pneumonia treatment (baseline) and then annually until study completion and correlate these measurements with lung function tests and chest CT performed at the same time-points, strengthening the causal inferences in Aims 1 & 2 and setting the foundation for future trials of therapeutic interventions. (End of Abstract)